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Hypermethylation-associated Inactivation of p14^ARF Is Independent of p16^INK4a Methylation and p53 Mutational Status¹

The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [M. E., M. T., S. B. B., J. G. H.]; Laboratori d’Investigacio Gastrointestinal, Hospital de la Santa Creu i Sant Pau, Barcelona, 08025 Spain [G. C.]; and Institut de Recerca Oncologica, Hospital Duran i Reynals, Barcelona, 08907 Spain [S. T., M. A. P.]

The INK4a/ARF locus encodes two cell cycle-regulatory proteins, p16^INK4a and p14^ARF, which share an exon using different reading frames. p14^ARF antagonizes MDM2-dependent p53 degradation. However, no point mutations in p14^ARF not altering p16^INK4a have been described in primary tumors. We report that p14^ARF is epigenetically inactivated in several colorectal cell lines, and its expression is restored by treatment with demethylating agents. In primary colorectal carcinomas, p14^ARF promoter hypermethylation was found in 31 of 110 (28%) of the tumors and observed in 13 of 41 (32%) colorectal adenomas but was not present in any normal tissues. p14^ARF methylation appears in the context of an adjacent unmethylated p16^INK4a promoter in 16 of 31 (52%) of the carcinomas methylated at p14^ARF. Although p14^ARF hypermethylation was slightly overrepresented in tumors with wild-type p53 compared to tumors harboring p53 mutations [19 of 55 (34%) versus 12 of 55 (22%)], this difference did not reach statistical significance. p14^ARF aberrant methylation was not related to the presence of K-ras mutations. Our results demonstrate that p14^ARF promoter hypermethylation is frequent in colorectal cancer and occurs independently of the p16^INK4a methylation status and only marginally in relation to the p53 mutational status.

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